The clinical advantages of controlled and patterned delivery of therapeutic agents are well established in the art. Many of the desirable attributes of controlled release pharmaceutical preparations stem from their ability to deliver predetermined quantities of one or more active agent(s) with a high degree of precision over a desired time frame.
Delivery devices and systems for the controlled release of active agents are generally characterized as either diffusion controlled delivery systems; erosion controlled systems, osmotic dispensing devices, or combinations of diffusion and erosion control. These devices and systems are derived from various compositions and techniques such as matrix processes, core embedding processes, coating processes as well as osmotically activated processes. Exemplifying these delivery devices are a broad range of systems from time release capsules whose contents have coatings that erode at different rates, diffusion-controlled matrix tablets with hydro-swellable barriers, and controlled release-rate tablets which operate by osmosis. Irrespective of the mechanism underlying the controlled release of an agent of interest, it is desired that a delivery system be characterized by a constant and reproducible in-vivo pharmacokinetic response facilitated by zero-order release kinetics (i.e. where the release of an agent of interest, for example a pharmaceutical agent, is independent of its own concentration).
U.S. Pat. Nos. 4,601,894, 4,687,757, 4,680,323, 4,994,276 disclose controlled release delivery devices based on matrix systems. These matrix systems are generally known to lack the ability to release pharmaceutical agents according to zero-order kinetics. (e.g. S. D. Bruck, Controlled Drug Delivery, Vol. I and II, CRC Press (1983)).
Core embedding or core coated delivery systems have been disclosed, for example in U.S. Pat. No. 3,538,214. This document describes a diffusion-controlled device in which a tablet core containing the active ingredient, is surrounded by a water insoluble coating. The insoluble film coating has been modified with modifying agents that are soluble to the external fluids in the gastrointestinal tract.
U.S. Pat. Nos. 3,845,770 and 3,916,899 disclose osmotic devices comprising a core composition of an active agent in combination with an osmotically effective solute, that is enclosed by an insoluble semi-permeable wall having a release capacity. The release characteristics of these devices have been improved through modifications disclosed, for example, in U.S. Pat. Nos. 4,624,847, 5,082,668. In principle, osmotic delivery employs one or more osmotic pressure adjuvants, for example a salt, and one or more components involved in expansion, for example a polymer, to deliver an agent of interest to a fluid environment over a period of time. The osmotic pressure adjuvants present in the delivery device are used to cause the influx of water by osmosis, through a semi-permeable wall, while the component involved with expansion absorbs liquid, expands, and acts to drive out the agent of interest from the interior of the osmotic device in a controlled and constant manner. Such systems are capable of zero-order release kinetics.
A disadvantage with coated delivery systems as well as osmotic devices, is that any damage to the wall or shell results in the premature release of the pharmaceutical agent within a short period of time causing what is known in the art as “dose dumping”. Patient safety is jeopardized as a result of side effects and possible toxicity from high levels of an agent of interest, for example a pharmacological agent, being released within the blood stream over a short period of time.
While attempts have been made to minimize the safety risks associated with conventional single unit delivery devices by developing multiple unit osmotic pumps, these embellishments have led to increased manufacturing costs (e.g. S. D. Bruck, supra). Similarly, osmotic delivery systems typically comprise one or more openings for the passage of an agent from the delivery device to the environment. The manufacture of the openings within the delivery device may be carried out using one or more laser drills (e.g. U.S. Pat. Nos. 3,845,770 and 3,916,899). The additional steps and machines required for the manufacture of fixed openings within the delivery device also increase the cost of manufacture of such delivery devices.
While delivery systems have been designed that reduce the risk levels to the patient, there still remains significant and inherent shortcomings in osmotic devices, in part due to their reliance on the need for an osmotic gradient to be established between the contents of the device and the fluid environment as well as the need for fixed opening(s) for the delivery of the agent. A blockage of the opening(s) either during storage or handling prior to patient consumption or due to the imminent interaction with dietary contents such as solid food particulate, or simply due to adherence to the gastrointestinal cell wall, will alter the osmotic gradient and severely impair the performance of the osmotic device.
In addition, fluctuating osmolarity in the environment of use, such as the human gastrointestinal tract, impacts on the reproducibility and performance of osmosis-dependent devices. It is well known that the osmolarity of human gastro-intestinal fluid is imminently variable in the fed and fasted states. There can be a substantial increase of up to two fold in the fed state within the individual (J. B. Dressman, Physiological Aspects of the Design of Dissolution Tests, Scientific Foundation for Regulating Drug Product Quality—AAPS Press 1997). These natural variables are further pronounced by diets containing varying salt and electrolyte contents. The performance of osmotically driven delivery devices is dependant upon many physiological variables and the dietary habits of patients. For example, side effects within patients (the “flame-cutter effect”) arising from the concentrated release of a pharmaceutical agent from the release opening(s) of osmotic systems has led to the withdrawal of preparations comprising Indomethacin.
Additionally, some active agents possess chemical properties that are comparable in ionic strengths to those of strong electrolytes and salts commonly used as osmotic adjuvants. In these instances, and due to different pH environments in the gastrointestinal tract, agents comprising significant ionic strength will manifest varying degrees of ionization that may compromise the predictable performance of the osmotic device. Osmotically active therapeutic agents with ionic strengths comparable to that of osmotic adjuvants, and that are localized within osmotically driven devices, will act as osmotic agents and enhance the osmotic influx of water from the fluid environment. Similarly, agents having high ionic strength may also cause variations in the osmolarity of the adjacent fluid environment upon their release from the delivery device. Therefore, osmotically-driven devices comprising agents characterized as having a high ionic strength, lack self-regulation.
A delivery system that is not readily influenced by minor changes to its physical form, intrinsic properties of an active agent (e.g. ionic strength), or variables in the environment of use (e.g. varying osmolarity of the human gastrointestinal tract and factors such as the dietary contents), can be reliably programmed to deliver the agent in a pre-determined manner with increased accuracy and precision. Therefore, there remains within the art a need for a reliable zero-order drug delivery system, where the release of an agent is independent of its own concentration, that provides controlled drug delivery of an active agent to an environment of use and that is independent of physiological variables of the environment of use, as well as the intrinsic properties of the active agent.
It is an object of the invention to overcome disadvantages of the prior art.
The above object is met by the combinations of features of the main claims, the sub-claims disclose further advantageous embodiments of the invention.